No description available.

von Willebrand Disease (VWD) is the most common inherited bleeding disorder in humans, resulting from quantitative or qualitative deficiencies of von Willebrand factor (VWF). Type 3 VWD is the rarest and most severe form of the disease. This thesis characterizes the phenotype-genotype correlations of a cohort of Canadian type 3 VWD patients and their family members. Three main findings are highlighted: 1) 50% of families showed evidence of co-dominant inheritance as opposed to recessive, 2) 42% of mutations identified were located in the VWF propeptide region (VWFpp), 3) index cases (IC) with mutations in the VWFpp had a more severe bleeding diatheses than IC with mutations elsewhere. We investigated two of the identified VWFpp mutations (ex4-5del and Cys633Arg) to elucidate their molecular mechanisms using two cellular models. Patient-derived blood outgrowth endothelial cells (BOEC) are ideal for studying the underlying molecular mechanism of VWF mutations as they represent the native vascular endothelium. BOEC were isolated from type 3 VWD IC and family members with the mutations of interest. A heterologous cellular system was also used to study the VWF mutations in vitro. The VWFpp mutations caused impaired VWF secretion, defective multimerization, qualitative and quantitative defects in Weibel-Palade body (WPB) formation, and resulted in VWF retention within the endoplasmic reticulum. We attempted to restore secretion and multimerization by co-transfecting each mutant with the wild-type VWF propeptide (VWFpp), which was unsuccessful. Additionally, we investigated a third mutation, c.8419_8422dupTCCC, which is unique to the Canadian VWD population and is found at a high frequency in a specific geographic population. While we hypothesized that this mutation would disrupt dimerization due to its location in the C-terminal cysteine knot (CK) domain of VWF we did not find this to be true. The results presented within this thesis provide new insight into the genetics and pathobiology of type 3 VWD, the functional contribution of the VWFpp to type 3 VWD and highlight the utility of BOEC as a cellular model for evaluating the pathogenic mechanisms of VWF mutations. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-10-17 21:15:37.685

Background As a major cause of morbidity and mortality treatment of venous thromboembolism is important, with the correct use of anticoagulants it is possible to greatly reduce both mortality and morbidity. Warfarin is among the most widely used anticoagulants being effective in treatment and prevention of venous thromboembolism with few negative side effects other than bleeding complications. With a narrow therapeutic window warfarin treatment requires constant monitoring and adjustments to stay effective without an increased bleeding risk. The aim of this thesis was to study the efficacy and safety of warfarin treatment in venous thromboembolic disease. Methods Using AuriculA, the Swedish national quality register for atrial fibrillation and anticoagulation, a cohort was created of patients registered with warfarin treatment during the study time January 1st 2006 to December 31th 2011, including all different indications for anticoagulation. In all four studies the study design was retrospective with information added to the cohort from the Swedish national patient register about background data and endpoints in form of bleeding complications in all studies and thromboembolic events in study 1 and 2. In study 3 and 4 information was added from the cause of death register about occurrence of death and in study 3 cause of death. In study 3, information from the prescribed drugs register about retrieved prescriptions of acetylsalicylic acid was added. Results In study 1 the mean TTR was found to be high both among patients managed at primary healthcare centres and specialised anticoagulation clinics at 79.6% and 75.7%. There was no significant difference in rate of bleeding between the two types of managing centres being 2.22 and 2.26 per 100 treatment years. In study 2 no reduction in complication rate with increasing centre TTR was seen for patients with atrial fibrillation with few centres having centre TTR below 70% (2.9%), in contrast to previous findings by Wan et al(1). For those with warfarin due to VTE where a larger proportion of the centres had centre TTR below 70% (9.1%) there was a reduction in complication rate with increasing centre TTR. Among the 13859 patients with treatment for VTE in study 3 age (HR 1.02, CI 95% 1.01-1.03), hypertension (HR 1.29, CI 95%1.02-1.64), Cardiac failure (HR 1.55, CI 95% 1.13-2.11), chronic obstructive pulmonary disease (HR 1.43, CI 95% 1.04- 1.96), alcohol abuse (HR 3.35, CI 95% 1.97-5.71), anaemia (HR 1.77, CI 95% 1.29-2.44) and a history of major bleeding (HR 1.75, CI 95% 1.27-2.42) increased the risk of bleeding during warfarin treatment. In study 4 both those with high iTTR and those with low INR variability had a low rate of bleedings at 1.27 (1.14-1.41) or 1.20 (0.94-1.21) per 100 treatment years compared to those with low iTTR and high INR variability having a rate of bleeding at 2.91 (2.61-3.21) or 2.61 (2.36-2.86) respectively. Those with the combination of both low iTTR and high INR variability had an increased risk of bleeding, hazard ratio HR 3.47 (CI 95 % 2.89-4.17). The quartile with both the lowest iTTR and the highest INR variability had an increased risk of bleeding with a hazard ratio 4.03 (3.20-5.08) and 3.80 (CI 95%, 3.01-4.79) compared to the quartile with the highest iTTR and lowest INR variability. Conclusion It is possible to achieve a safe warfarin treatment both in specialised anticoagulation centres and in primary health care. At initiation of treatment some of the patients at high risk of bleeding can be identified using knowledge about their background. With the use of quality indicators as TTR and INR variability during treatment those at high risk of complications can be identified and analysing treatment quality on centre level gives an opportunity to identify improvement areas among managing centres. With the addition of new treatment options warfarin can still be the most suitable option for some patients, being safe and effective when well managed.

Abnormal uterine bleeding (AUB) is one of the most common presenting complaints in our medical system with up to 30% of females affected by this condition. The current evaluation and management of AUB often requires multiple lengthy visits to both general practitioners and specialists. Advances in endoscopic technology have allowed clinicians to diagnose and treat women presenting with AUB in a single-visit within an outpatient uterine assessment and treatment unit (UATU). Unfortunately, the UATU is not the standard of care with very few locations in Canada providing this type of service. This thesis project aimed to synthesize data pertaining to efficacy and safety as well as to evaluate the cost-effectiveness of a UATU service model compared to usual care in diagnosing and treating AUB. To address the main aim for this thesis project, the first manuscript focuses on the hysteroscopic procedures that may be offered in a UATU. The manuscript includes a systematic review that synthesizes outcome measures surrounding efficacy, patient safety, and cost data of outpatient hysteroscopy compared to hysteroscopy performed in the operating room. The second manuscript is a cost-effectiveness modelling study that compares cost and effectiveness outcomes, including time to diagnosis and time to treatment of a UATU versus usual care for women who present with AUB. Data used to populate the cost-effectiveness model were obtained from a retrospective review of patient charts and the published literature. The systematic review found no statistically significant difference in the safety, efficacy, or patient tolerability between outpatient and intraoperative hysteroscopy procedures. This review helps provide further support for performing procedures outside of a traditional operating room without increasing patient harm or compromising efficacy. However, given the current available evidence and limited number of studies, findings should be interpreted with caution. The cost-effectiveness analysis found that a UATU is cost-effective when compared to usual care in diagnosing and treating patients who present with AUB. These two studies combined provide evidence to support that the UATU has the potential to improve gynecologic care by reducing wait-times to receiving diagnosis and treatment and to lower overall costs to the health care system.

Au vu de la différence de densité entre les composants minéraux solides et l’eau entrant dans la composition d’un béton, une instabilité gravitaire peut apparaître et provoquer une séparation de phase. Cette séparation est à l’origine de la formation d’une pellicule d’eau à la surface du béton et est appelé ressuage. Malgré le fait que le ressuage peut directement ou indirectement nuire aux propriétés finales du béton durci, les connaissances existantes ne permettent pas de prédire ce phénomène ou de le corréler à la formulation du béton. L’objectif de cette thèse est d’identifier la physique mise en jeu lors du phénomène de ressuage de façon à proposer à la fois une méthodologie de mesure adaptée et un cadre théorique prédictif.La démarche retenue consiste à commencer par l’étude d’un matériau simple tel qu’une pâte de ciment en laboratoire pour terminer à l’échelle plus complexe d’un béton de fondation coulé sur chantier.Dans une première partie, nos résultats expérimentaux sur pâte de ciment suggèrent que le ressuage ne peut pas être considéré comme un simple phénomène de consolidation homogène d'un matériau poreux déformable mais comme un phénomène de consolidation hétérogène conduisant à la formation de canaux préférentiels d'extraction d'eau. Nous montrons ainsi l'existence de trois régimes de ressuage : une période d'induction, une période d’accélération et une période de consolidation. Seuls les deux derniers régimes avaient été observés et discutés jusqu'à maintenant dans la littérature. Nos résultats suggèrent que la formation de ces canaux préférentiels semble être initiée par les défauts du système (les bulles d’air au premier ordre).Dans une seconde partie, les deux essais normalisés utilisés à ce jour dans la pratique industrielle pour la mesure du ressuage des bétons sur chantier, l’essai ASTM et l’essai Bauer, sont étudiés. Nous montrons que ces essais capturent des aspects différents du ressuage et qu’ils ne peuvent donc être corrélés. Nous montrons par ailleurs l’existence de limites dans la capacité de ces essais à capturer le risque de ressuage pour un béton donné. Des modifications de protocole sont alors proposées pour améliorer ces essais et leur permettre de fournir les données nécessaires à la prédiction du ressuage à l’échelle de la fondation.Enfin, nous étudions à la fois les différences entre ressuage d’une pâte de ciment et ressuage d’un béton et l’influence de la hauteur totale de matériau soumis au ressuage. La forte dépendance de la vitesse de ressuage à la profondeur est mise en évidence dans le cas des bétons. Un modèle permettant d’extrapoler une vitesse de ressuage dans une fondation à partir d’une mesure de ressuage à l’aide de l’essai ASTM est proposé. Ce modèle est validé sur des essais de laboratoire et des fondations réelles.Mots clés : ressuage, béton, pâte de ciment, consolidation, effet d’échelle / Due to the density differences between the solid mineral components and the suspending water, gravity can induce phase separation in concrete. This phase separation is at the origin of the formation of a film of water on the upper surface of fresh concrete, commonly known as bleeding. Although bleeding is known to directly or indirectly affect the final properties of hardened concrete, the existing knowledge does not allow for the prediction of this phenomenon or its correlation to mix proportions. The objective of this thesis, therefore, is to identify the physics behind the bleeding phenomenon in order to propose both an adapted measurement methodology and a predictive theoretical framework.The approach adopted is to start from the study of a simple model material, a cement paste in the laboratory, and upscale to the more complex scale of concrete poured into a real foundation on site.In the first part, our experimental results on cement paste suggest that bleeding cannot be simply described as the consolidation of a soft porous material, but, in fact, is of an obvious heterogeneous nature leading to the formation of preferential water extraction channels within the cement paste. We thus show the existence of three bleeding regimes: an induction period, an acceleration period, and a consolidation period. Only the last two regimes had been observed and discussed in the literature. Our results suggest that the formation of these preferential channels seems to be initiated by system defects (air bubbles at first order).In the second part, the two industrial standard tests used for the measurement of bleeding on site, the ASTM test and the Bauer test, are studied. We show that these tests capture different aspects of bleeding, and therefore, cannot be correlated. We also show the existence of limits in the capacity of these tests to capture the risk of bleeding for a given concrete. Changes and improvements are proposed in order to enable these tests to provide the data necessary for the prediction of bleeding at the concrete foundation scale.Finally, in the last part, we study the differences between the bleeding of a cement paste and the bleeding of a concrete and the influence of the total height of material subjected to bleeding. The high dependence of the bleeding rate on the depth of the foundation is captured in the case of concretes. A model is proposed to extrapolate a bleeding rate in a foundation from a bleeding measurement using the ASTM test. This model is validated on laboratory tests and on onsite measurements of real concrete foundations.Keywords: bleeding, concrete, cement paste, consolidation, scale effect

The clinical management of Factor XI (FXI) deficiency is problematic due to the marked phenotypic heterogeneity between individuals with this disorder and the lack of a reliable test to predict bleeding risk. FXI-deficient individuals are currently at risk of being over- or under treated, with associated risks of transfusion-related complications or haemorrhage respectively. The improvement of care of FXI-deficient patients requires the development of measures that can predict bleeding phenotype and enable the identification of individuals who need treatment at times of haemostatic challenge. In addition, for those requiring treatment, there is a need for development of tests which can determine the optimal type and dose of FXI replacement on an individually tailored basis, as well as assays which can accurately monitor the effect of treatment and guide clinicians in the requirement for further perioperative treatment. This thesis addresses these objectives by studying global haemostasis assays and bleeding scores as tools to predict bleeding tendency and by studying the utility of global haemostasis assays as potential tests by which FXI replacement treatment can be determined and monitored. For prediction of bleeding tendency, this research demonstrated that the thrombin generation assay (TGA) was able to differentiate bleeding tendency provided the sample conditions used in the assay were optimised to assess FXI involved coagulation pathways thought to be of relevance in vivo: using platelet rich plasma with inhibition of in vitro contact activation and a low tissue factor trigger. Thromboelastometry measured using the same sample type was similarly able to distinguish bleeding phenotype. However, when the potential clinical utility of the assays was compared using receiver operating characteristic curve analysis, thromboelastometry was inferior to TGA as an identifier of bleeding tendency. When the thromboelastometry sample type used was whole blood, or where assays were performed in the presence of tissue plasminogen activator the assays did not differentiate bleeding phenotype. For purposes of treatment planning, the potential of the TGA to determine the optimal dose of FXI replacement was assessed by in vitro spiking experiments using two commercially available FXI concentrates and samples from individuals with major FXI deficiency. Each concentrate improved thrombin generation, but dose response curves were found to differ, suggesting different properties for the two products. The clinical utility of the approach was then demonstrated with comparable TGA results obtained in ex vivo samples from patients treated with FXI concentrate and baseline samples spiked in vitro with equivalent amounts of the same FXI concentrate. The utility of global haemostasis assays to monitor the effect of FXI replacement in FXI-deficient individuals undergoing surgery was also tested. Improvement in assay parameters after treatment with solvent-detergent fresh frozen plasma or FXI concentrate was demonstrated suggesting assay value in FXI replacement monitoring. Finally the use of recently developed bleeding assessment tools and bleeding scores as descriptive, diagnostic or predictive measures was tested along with correlation with FXI:C levels and TGA parameters. This analysis confirmed that bleeding scores have a limited value in the clinical assessment of FXI deficiency.

It is new experimental graphic work, made by installation , mixed graphic technology’s and music. The important view of work is presentation of idea. “bleeding”-is process of microcerculaishen spreader of metaphysical energy, is like autonomic world, but depends of mikro and macro humming.The abstrakt world becomes understanding just resettlement in the whole.

No description available.

Introduction Citalopram is a preferred medication used for the treatment of depression and belongs to a group known as selective serotonin reuptake inhibitors (SSRI). When used on a long-term basis, it leads to a significant decrease of serotonin in thrombocytes. Citalopram-treated patients often display haemorrhagia that is explained by its anti-platelet effect, which is also - more or less - the case for other medications from the SSRI group. Aim of the Thesis The aim of the thesis was to find out: a) Whether citalopram treatment (2 weeks) has influence on the plasma concentration of thromboxane B2; b) Whether there is a relation between the expected decrease of thromboxane B2 levels and the plasma concentration of citalopram. Methods and Patient Population We carried out clinical and laboratory tests on a study population consisting of elderly and polymorbid patients who underwent a 14-day citalopram treatment with daily doses of 20mg. Among other tests, we observed the plasma concentration of thromboxane and citalopram. Out of 160 patients examined, 78 patients were assessed. Results Our study has proved that even a short-term citalopram treatment results to a significant increase in the plasma concentration of thromboxane B2 and the suppression rate of thromboxane B2 correlates with the higher...

Orientador: Ilza Maria Urbano Monteiro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-19T23:33:10Z (GMT). No. of bitstreams: 1 Makuch_MariaValeriaBahamondes_D.pdf: 16535785 bytes, checksum: be3709b6137735be64ac9a6dfffdc1a5 (MD5) Previous issue date: 2012 / Resumo: Introdução: O sistema intrauterino liberador de levonorgestrel (SIU-LNG) é um contraceptivo altamente efetivo com benefícios não contraceptivos, entre eles o tratamento da menorragia. Restam dúvidas sobre o uso do SIU-LNG em mulheres nuligestas, especialmente no tocante à taxa de expulsão e o custo-beneficio para o tratamento da menorragia quando se compara com tratamentos cirúrgicos. Os objetivos deste estudo foram avaliar a facilidade de inserção e o desempenho clínico do SIU-LNG em mulheres nuligestas durante um ano de seguimento; verificar a correlação entre o comprimento da cavidade uterina e as taxas de expulsão em usuárias de dispositivo intrauterino com cobre (DIU TCu380A) e de SIU-LNG, e avaliar os recursos e procedimentos envolvidos na inserção do SIU-LNG quando comparado à realização da histerectomia em mulheres com menorragia atendidas em um hospital público do Brasil. Métodos: Foi feito o seguimento de duas coortes de mulheres que inseriram o SIU-LNG no mesmo dia, 159 nuligestas e 477 mulheres com filhos, pareadas na razão1:3. A inserção foi classificada em fácil ou difícil, e quando foi difícil avaliou-se o uso de velas de Hegar ou misoprostol, e as falhas de inserção foram registradas separadamente. O segundo estudo admitiu 235 mulheres nuligestas e mulheres com filhos que inseriram o DIU TCu380A ou o SIU-LNG, com o seguimento de um ano. O comprimento da cavidade uterina foi medido por histerometria e por ultrassom, e a taxa de expulsão foi correlacionada com o tamanho uterino. O terceiro estudo teve duas coortes de mulheres com menorragia, mulheres que inseriram o SIU-LNG (n=124) pareadas com mulheres que realizaram uma histerectomia (n=122). Avaliamos o número de procedimentos realizados em cada grupo antes de escolherem o tratamento, os que foram realizados para a inserção do SIU-LNG e/ou histerectomia, e os procedimentos decorrentes das complicações registradas após um ano de seguimento. Resultados: Em quase 80% dos casos não foi encontrada dificuldade na inserção do SIU-LNG e o uso de dilatadores e misoprostol não foi frequente; entretanto, o uso de dilatadores foi três vezes maior no grupo das nuligestas. Houve uma falha da inserção no grupo de nuligestas e duas no grupo de mulheres com filhos. Não houve uma única gravidez, a taxa de expulsão foi de aproximadamente 4/100 mulheres/ano e a taxa de continuação do método foi superior a 90%, em ambos os grupos, após um ano de seguimento. A medida do comprimento da cavidade uterina foi menor que 3,2cm em 2 usuárias e de pelo menos 3,2cm de comprimento em 87 usuárias de SIU-LNG, com taxas de expulsão de 0 (0,0%) e 2 (2,3%), respectivamente (p>0,999). A média de comprimento da cavidade uterina foi de 3,9cm ± 0,3cm por ultrassom entre as 10 mulheres que expulsaram o dispositivo, comparada com a média de comprimento de 3,9 ± 0,0cm naquelas que não expulsaram o dispositivo (p=0,799). No terceiro estudo, a idade e duração da menorragia foram significativamente menores no grupo de usuárias de SIU-LNG do que no grupo de mulheres que realizaram histerectomia. Os números de consultas ginecológicas e de coleta de citologia oncológica foram levemente maiores no grupo do SIU-LNG, mas as mulheres que realizaram histerectomia realizaram testes mais complexos, como exames de laboratório, ultrassom, radiografia de tórax e eletrocardiograma. No grupo da histerectomia as principais complicações foram: hemorragia (6), perfuração de bexiga/intestino (4), complicações anestésicas (1), reimplantação ureteral (1) e dor abdominal (2). Aos 12 meses de seguimento, a menorragia foi controlada em 83,1% das mulheres no grupo do SIU-LNG e 106 mulheres continuaram usando o dispositivo. Conclusões: O SIU-LNG mostrou-se um método seguro para uso em mulheres nuligestas. A inserção é um procedimento simples e o desempenho clínico foi bom em mulheres com e sem filhos. O comprimento da cavidade uterina não foi associado a maior risco de expulsão do SIU-LNG. Ambos os tratamentos, SIU-LNG e histerectomia, foram efetivos para controlar a menorragia. O grupo de usuárias de SIU-LNG usou menos recursos e teve menos complicações que o grupo da histerectomia. O SIU-LNG mostrou-se um bom método para reduzir o número de histerectomias e de recursos usados no tratamento de mulheres com menorragia / Abstract: Background: Despite the high contraceptive efficacy and the additional non-contraceptive benefits such as treatment of heavy menstrual bleeding (HMB) of the levonorgestrel-releasing intrauterine system (LNG-IUS), concerns persist with respect to its use in nulligravidas, the expulsion rate in this group and the cost-effectiveness when compare to surgical treatments in the treatment of HMB. The objectives of this study were to evaluate the ease of insertion and clinical performance of the LNG-IUS in nulligravida women up to one year after insertion; the correlation between endometrial cavity length and expulsion rate in acceptors of the TCu380A intrauterine device (IUD) or LNG-IUS; and to evaluate the resources and procedures involved in the placement of an LNG-IUS compared to performing hysterectomy in women with HMB in a public sector hospital in Brazil. Methods: Two cohorts were formed following LNG-IUS insertion, one consisting of 159 nulligravidas and the other of 477 parous women. Each nulligravida women was paired with 3 parous women who had an LNG-IUS inserted on the same day. Insertion was classified as easy or difficult and when classified as difficult, the use of Hegar dilators and/or misoprostol, and insertion failure were also recorded. The second study included 235 nulligravida and parous women who received a TCu380A IUD or LNG-IUS and who were followed up to 1 year. The length of the uterine cavity was measured by uterine sounding and ultrasonography, and the expulsion rate was correlated to uterine size. The third study had two cohorts of women: women who accepted an LNG-IUS (n=124) and a matched woman who underwent hysterectomy on the same day (n=122), due to HMB. We evaluate the number of procedures carried out in each group of women, including those performed before the decision was made to insert an LNG-IUS or to perform hysterectomy, the insertion of the device itself and the surgical procedure and the procedures and complications registered up to one year after LNG-IUS insertion or hysterectomy. Results: In almost 80% of cases, no difficulty was encountered during insertion, and dilators and misoprostol were seldom required; however, when necessary, dilator use was almost three-fold higher in nulligravida women. Insertion failed in one nulligravida women and in two parous women. The clinical performance of the device showed zero pregnancy rate, expulsion rates of ~4/100 women/year and one-year continuation rate of over 90% in both groups. When we measured the endometrial cavity, we showed that it was shorter than 3.2 cm in 2 LNG-IUS users and at least 3.2 cm long in 87 LNG-IUS users, with expulsions occurring in 0 (0.0%) and 2 (2.3%) of these women, respectively (p>0.999). The mean length of the endometrial cavity evaluated by ultrasonography among the 10 women whose devices were expelled was 3.9 ± 0.3 cm, compared with 3.9 ± 0.0 cm in those who retained their devices (P=0.799). On the third study, age and the duration of HMB were significantly lower in the LNG-IUS acceptors than women at the hysterectomy group. The number of gynecological consultations and Pap smears were similar in both groups; however, women in the hysterectomy group also underwent laboratory tests, ultrasonography, chest X-ray and electrocardiogram. In the hysterectomy group, the main complications were: hemorrhage (6), bladder/bowel perforation (4), complications with anesthesia (1), ureteral reimplantation required (1) and abdominal pain (2). At one year, HMB was controlled in 83.1% of women in the LNG-IUS group and 106 women continued with the device. Conclusions: The LNG-IUS was suitable for use by nulligravidas. It is simple to insert and its clinical performance in nulligravidas was similar to that found in parous women. The length of the endometrial cavity do not support the hypothesis of an association between uterine length and risk of LNG-IUS expulsion. Both treatments were effective in HMB control. Fewer resources and complications were observed in LNG-IUS acceptors when compared to hysterectomy. The LNG-IUS represents a good strategy for reducing the number of hysterectomies and the resources required for women with HMB / Doutorado / Fisiopatologia Ginecológica / Doutor em Ciências da Saúde